Novel agent may be effective in diabetic eye disease

AKB-9778 could change treatment approach

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A novel agent, AKB-9778, administered by subcutaneous injection appears to be effective in the treatment of diabetic eye disease alone or in combination with anti-vascular endothelial growth factor (anti-VEGF), reported Arshad Khanani MD, MA, Managing Partner, Sierra Eye Associates, and Clinical Associate Professor, University of Nevada, USA, at the 34th Annual Meeting of the American Society of Retina Specialists in San Francisco. Dr Khanani explained that Tie2 is a transmembrane receptor expressed almost exclusively on vascular endothelial cells and that activated Tie2 is essential for vascular stability. Downregulation of Tie2 activity occurs in abnormal vasculature including in diabetic retinopathy (DR), macular degeneration and retinal vein occlusion. AKB-9778 acts by inhibiting VE-PTP, a critical negative downregulator of Tie2. Dr Khanani presented the results of the TIME-2 study, a prospective phase II trial that evaluated the effects of subcutaneous injection of AKB-9778 (Aerpio Therapeutics) on diabetic macular oedema (DME) and DR in 144 patients. Study participants all had baseline central subfield thickness (CST) of at least 325μm in the study eye at enrollment. Pre-treatment visual acuity ranged from 20/32 to 20/400. The primary endpoint of the trial was change in CST from baseline. Another key endpoint was the percentage of patients that achieved a ≥ 2-step improvement in diabetic retinopathy severity score (DRSS) in the study and fellow eye. The TIME-2 trial randomised patients to one of three different arms - subcutaneous AKB-9778 15mg BID along with a sham intravitreal injection; a combination of AKB-9778 15mg BID with intravitreal ranibizumab 0.3mg; or a placebo subcutaneous injection along with intravitreal ranibizumab 0.3mg. Patients in the study were treated for three months and then observed for an additional two months. “The study found no significant baseline change in CST with AKB-9778 monotherapy, but there was a significant decrease in CST seen with combination therapy with AKB-9778 and ranibizumab compared to ranibizumab alone (-163.8 ± 24.3µm versus -109.2 ± 17.2µm, respectively),” reported Dr Khanani. Due to its short duration, the TIME-2 study was not powered to show a statistically significant difference in visual acuity between the groups. However, the data showed a trend favouring the combination treatment arm, he added. Moreover, the treatment responses did not appear to be driven by outliers, he added. There was a significant decrease in macular oedema in each patient in the combination arm when compared to the monotherapy arm. A pre-specified analysis of DRSS was also performed using seven-field fundus photographs by masked graders. The percentage of study eyes achieving ≥ 2-step improvement from baseline was equal in all three treatment groups. Interestingly, fellow eyes of patients treated with AKB-9778 also showed significant improvement in DRSS that were equivalent to the results seen in the study eye, suggesting potential activity of AKB-9778 in both eyes, noted Dr Khanani. “With its less invasive route of administration, compared to intravitreal injections, and the potential to treat both eyes, AKB-9778 could change the way we approach the treatment of diabetic eye disease,” Dr Khanani added. The next study of AKB-9778 will be in patients with non-proliferative DR and no DME. Arshad Khanani: arshad.khanani@gmail.com